影响 Kir4.1 通道的 KCNJ10 杂合子变异导致阵发性运动性障碍。

IF 7.4 1区医学 Q1 CLINICAL NEUROLOGY Movement Disorders Pub Date : 2024-10-05 DOI:10.1002/mds.30025

Xiaojun Huang, Xin Fu, Jingying Wu, Xin Cheng, Xiaoqi Hong, Ziyi Li, Lan Zheng, Qing Liu, Shendi Chen, Beisha Tang, Yuwu Zhao, Xiaorong Liu, Xunhua Li, Xiaoli Liu, Zaiwei Zhou, Li Wu, Kan Fang, Ping Zhong, Mei Zhang, Xinghua Luan, Wotu Tian, Xiaoping Tong, Li Cao

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引用次数: 0

摘要

背景：60%的阵发性运动障碍（PKD）病例属于不确定变异型：60%以上的阵发性运动障碍（PKD）病例属于不确定变异型：目的：阐明导致PKD的新的遗传因素：方法：共招募了476名遗传原因不确定的患者进行全外显子组测序。采用病例对照分析方法确定候选基因。采用全细胞膜片钳记录法验证已确定变异的电生理影响。通过注射腺相关病毒建立了候选基因小脑杂合子敲除小鼠模型，并进行了肌张力障碍样表型诱导和旋转体试验。应用体内多单元电记录研究了基因敲除小鼠神经兴奋性的变化：结果：研究人员对PKD患者和对照组的钾内向整流通道J亚家族成员10（KCNJ10）杂合子变异进行了比较。在522名受试者中，有16人检测到15个变体（频率=3.07%）。与PRRT2（富脯氨酸跨膜蛋白2）变体患者相比，KCNJ10变体患者的表现往往较轻。KCNJ10 变体部分改变了内向整流钾通道 4.1（Kir4.1）的跨膜位置。Kcnj10 的表达与 PKD 的自然病程一致。Kcnj10的变异导致细胞Kir4.1电流不同程度的减少，小脑中Kcnj10杂合子条件性敲除的小鼠出现肌张力障碍姿势，同时运动协调性和旋转测试中的运动学习能力较差。Kcnj10-cKO小鼠小脑深核的发射率显著升高：我们发现了KCNJ10在PKD中的杂合变异。结论：我们在 PKD 中发现了 KCNJ10 的杂合变异，Kir4.1 的功能受损可能导致神经元兴奋性异常，从而引发 PKD。© 2024 国际帕金森和运动障碍协会。

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Heterozygous KCNJ10 Variants Affecting Kir4.1 Channel Cause Paroxysmal Kinesigenic Dyskinesia.

Background: More than 60% of paroxysmal kinesigenic dyskinesia (PKD) cases are of uncertain variants.

Objective: The aim was to elucidate novel genetic contribution to PKD.

Methods: A total of 476 probands with uncertain genetic causes were enrolled for whole-exome sequencing. A method of case-control analysis was applied to identify the candidate genes. Whole-cell patch-clamp recording was applied to verify the electrophysiological impact of the identified variants. A mouse model with cerebellar heterozygous knockout of the candidate gene was developed via adeno-associated virus injection, and dystonia-like phenotype inducement and rotarod tests were performed. In vivo multiunit electrical recording was applied to investigate the change in neural excitability in knockout mice.

Results: Heterozygous variants of potassium inwardly rectifying channel subfamily J member 10 (KCNJ10) clustered in PKD patients were compared with those in the control groups. Fifteen variants were detected in 16 of 522 probands (frequency = 3.07%). Patients with KCNJ10 variants tended to have a milder manifestation compared to those with PRRT2 (proline-rich transmembrane protein 2) variants. KCNJ10 variants partially altered the transmembrane location of inwardly rectifying potassium channel 4.1 (Kir4.1). The Kcnj10 expression is consistent with the natural course of PKD. Variants resulted in different degrees of reduction in cell Kir4.1 currents, and mice with heterozygous conditional knockout of Kcnj10 in the cerebellum presented dystonic posture, together with poor motor coordination and motor learning ability in rotarod tests. The firing rate of deep cerebellar nuclei was significantly elevated in Kcnj10-cKO mice.

Conclusion: We identified heterozygous variants of KCNJ10 in PKD. Impaired function of Kir4.1 might lead to abnormal neuronal excitability, which attributed to PKD. © 2024 International Parkinson and Movement Disorder Society.

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来源期刊

Movement Disorders 医学-临床神经学

CiteScore

13.30

自引率

8.10%

发文量

371

审稿时长

12 months

期刊介绍： Movement Disorders publishes a variety of content types including Reviews, Viewpoints, Full Length Articles, Historical Reports, Brief Reports, and Letters. The journal considers original manuscripts on topics related to the diagnosis, therapeutics, pharmacology, biochemistry, physiology, etiology, genetics, and epidemiology of movement disorders. Appropriate topics include Parkinsonism, Chorea, Tremors, Dystonia, Myoclonus, Tics, Tardive Dyskinesia, Spasticity, and Ataxia.